2-methoxyphenylpiperazine derivatives

ABSTRACT

The invention relates to fused heterocyclic compounds with ring junction nitrogen atom of the formula: ##STR1## wherein Q stands for 2-indolizinyl, 2-imidazo[1,2-a]pyridinyl, 2-imidazo[1,2-a]pyrimidinyl, 6-(2,3-dihydroimidazo[2,1-b]thiazol)-yl or 6-imidazo[2,1-b]thiazolyl group; and n is an integer from 2 to 4, as well as therapeutically useful salts thereof. The invention further relates to pharmaceutical compositions containing these compounds as well as a process for the preparation of the above compounds and compositions. The compounds of formula (I) exhibit mainly antipsychotic effects so the invention relates also to a method of treatment of schizophrenia, organic mental disorders, affective disorders, anxiety and personality disorders.

The invention relates to novel fused heterocyclic compounds with ringjunction nitrogen atom of a general formula (I) ##STR2## wherein Qstands for 2-indolizinyl, 2-imidazo[1,2-a]pyridinyl,2-imidazo[1,2-a]-pyrimidinyl, 6-(2,3-dihydroimidazo[2,1 -b]thiazol)-ylor 6-imidazo[2,1-b]-thiazolyl group; and

n is an integer from 2 to 4,

and to their therapeutically useful salts and pharmaceuticalcompositions containing these compounds. Furthermore, the inventionrelates also to a process for the preparation of the compounds offormula (I) and their therapeutically useful salts in such a way that ahaloalkyl ether derivative of formula (II) ##STR3## wherein Q and n areas defined above, and X means halogen is reacted with(2-methoxyphenyl)piperazine of formula (III). ##STR4##

The compounds of formula (I) according to the invention are novel andpossess significant biological activity, first of all antipsychoticeffects.

The invention relates also to a method of treatment, which comprisesadministering a therapeutically active amount of a compound of formula(I) or a therapeutically acceptable salt thereof to a patient to betreated.

Among the starting substances, some of chloroalkyl ether derivatives offormula (II) are known from the literature, such as3-[4-(2-imidazo[1,2-a]pyridinyl) -phenoxy]propyl chlorid,3-[4-(2-imidazo[1,2-a]pyrimidinyl)phenoxy]propyl chloride, or3-[4-(6-imidazo[2,1-b]thiazolyl)phenoxy]propyl chloride [J. Med. Chem.31, 2221 (1988)]. Other starting substances of formula (II) can beobtained according to the preparation process described in theabove-cited literature.

(2-Methoxyphenyl)piperazine of formula (III) is a known, commerciallyavailable substance.

Compounds structurally similar to the substances of formula (I) areknown from the literature. Such (substitutedamino)propoxyphenylimidazo[1,2-a]pyridines, substitutedamino)propoxyphenylimidazo[1,2-a]pyrimidines and (substitutedamino)propoxyphenylimidazo[2,1-b]thiazoles are described in theabove-cited publication [J. Med. Chem. 31, 2221 (1988)], however, unlikethe compounds according to the invention, these compounds possesscalcium channel-blocking and local anaesthetic effects.

In contrast to the structurally closely related compounds known from theliterature, the novel compounds of formula (I) according to theinvention are orally effective and are endowed of a considerableneuroleptic activitiy. Based on their biological activity, thesecompounds can be used as atypical antipsychotics, antidepressants,anxiolytics, neuroprotective and/or cognitive function improving agents,antiemetics or antiaddictives.

Since the 70's, antipsychotics have successfully been employed for thetreatment of schizophrenia. Up to the present haloperidol has been usedin the clinical practice most widely. Phenothiazines and haloperidolplayed a pioneering role in this therapeutic field and considerablycontributed to the development of the dopamine theory of schizophrenia.Later researches confirmed also the role of serotonine and a number ofother neurotransmitter systems, such as histaminerg, α-adrenerg,CCK-erg, etc. in this disorder. However, haloperidol and other typicalantipsychotics improve only the positive symptoms of the disease, e. g.hallucinations, delusions, agitation and thought disturbances, whereasnegative symptoms, such as emotional obtusion, autism, social isolation,neglection of personal hygiene remain unimproved. In addition, nearly30% of the patients do not respond to the treatment and a number ofundesired adverse effects cannot be excluded, either. From these, themost severe adverse effects are the appearance of extrapyramidalsymptoms (EPS), because of the strong but not regionselective antagonismof D-2 dopamine receptor, deterioration of cognitive functions caused byanticholinergic effect, orthostatic hypotonia (α-adrenerg antagonism),and hyperprolactinaemia.

Nowadays, intensive research is being devoted to atypicalantipsichotics, which are capable of improving both positive andnegative symptoms, do not induce extrapyramidal symptoms or only indoses higher than therapeutical, only a few non-responsive patientsshould be taken into account at all if any and other side effects arealso negligible. Clozapine, if did not cause agranulocytosis, could besuch an ideal antipsychotic.

Nowadays research is being focused on discovering clozapine-likeatypical antipsychotics. Clozapine-like action means that the moleculepossesses a strong antipsychotic effect without appearance of the aboveside effects. Such compounds have a direct or indirect selective actionon the dopaminergic pathways of limbo brain and this effect isassociated with a complex receptor profile. Within the complex receptorprofile, the D-2 receptor antagonistic effect characteristic ofhaloperidol is not dominant.

The novel compounds of formula (I) according to the invention exert anantispychotic effect similar to that of the atypical antipsychoticclozapin. Both antipsychotic and oral activites of the compounds wereconfirmed by a pomorphine-induced climbing and sniffing tests in vivo.The mechanism of action of the compounds was characterized by receptorbinding tests in vitro.

Inhibition of apomorphine (APO) induced climbing and sniffing

CD-1 (Charles River) male mice weighing 22 to 24 g were pretreated with1% Tween 80 solution of the compound to be tested. After 55 minutes, theanimals were placed two by two into examination cages [P. Potrais etal.: Psychopharmacol 50, 1-6 (1976)]. Six animals were used in eachgroup. At 60 minutes after pretreatment, the animals were treatedsubcutaneously with 1 mg/kg of apomorphine (APO). From the 10th to 25thminute following APO treatment the animals were scored in each minute asfollows: 0: all the four legs of the animal are on the ground; 1: theanimal climbs on the grid by its both forelegs; 2: the animal climbs onthe grid by all its four legs. The inhibitory effect was related to theAPO control group, which could achieve 32 scores as a maximum.

The inhibition of APO-induced sniffing stereotypy was measuredsimultaneously with the inhibition of climbing from the 10th to 25thminute following the APO administration according to S. Gerhardt [S.Gerhardt et al.: Life Sci. 37, 2355-2363 (1985)].

Receptor binding assays

D-2

Binding to the D-2 dopamine receptor was studied according to P. Seeman[P. Seeman et al.: J. Neurochem. 43, 221-235 (1984)] by using 0.5 nM ³H-spiperone as ligand; the non-specific binding was determined in thepresence of 10 μM(±)-sulphide.

5-HT1A

Determination of the 5-HT1A subtype of serotonin receptor was carriedout by a modification [M. D. Hall et al.: J. Neurochem. 44, 1685-1696(1985); H. Gozlan et al.: Nature 305, 140-142 (1983)] of the methoddescribed by Peroutka [S. J. Peroutka: J. Neurochem.47, 529-540 (1986)].0.5 nM ³ H-8-OH-DPAT was used as ligand, where non-specific binding wasdetermined by using 10 μM serotonin.

Alpha-1

The α-1 receptor activity of the compounds was measured according to themethod of Greengrass and Horung [P. Greengrass et al.: Eur. J. Pharmacol55, 323-326 (1979); R. Horung et al.: Naunyn-Schmiedeb. Arch Pharmacol.308, 223-230 (1979)] by using ³ H-prazosin as ligand. The non-specificbinding was measured with 10 μM (±)-phentolamine.

The results of the in vivo and in vitro investigations are summarized inTable 1, where

Q: A means 2-indolizinyl,

Q: B means 2-imidazo[1,2-a]pyridinyl,

Q: C means 2-imidazo[1,2-a]pyrimidinyl,

Q: D means 6-(2,3-dihydroimidazo[2,1-b]thiazol)-yl and

Q: E means 6-imidazo[2,1-b]thiazolyl group.

                                      TABLE 1                                     __________________________________________________________________________              ED.sub.50 (mg/kg p.o.)                                                        Inhibition of APO-                                                                     Inhibition of APO-                                                                         Receptor                                        Compound   induced induced Sniff./ IC.sub.50 (nM)                           No.   Q n climbing sniffing Climb.                                                                            D-2                                                                              5-HT1A                                                                            α-1                              __________________________________________________________________________    4510407                                                                             A 2 >>30     --       --  258                                                                              802 542                                      4510423 A 3 4.1 >10 >2.4 77 1000 359                                          4510613 A 4 14.8 >30 >2.0 99 243 842                                          4510408 B 2 2.4 ≈10 4.1 56 70 36                                      4510067 B 3 7.2 16.2 2.3 17 202 57                                            4510915 B 4 10.7 -- -- 69 21 34                                               4510411 C 2 3.4 >>30 >8.8 133 10 63                                           4510424 C 3 8.9 >>30 3.4 34 66 30                                             4510645 C 4 20.5 >>30 >1.5 55 12 22                                           4510471 D 2 6.3 >>30 4.8 117 29 75                                            4510473 D 3 15.3 >30 >2.0 29 122 48                                           4510991 D 4 ≈30 >>30 >1.0 56 9 16                                     4510470 E 2 0.8 4.5 5.6 73 38 101                                             4510472 E 3 3.4 ≈10 2.9 23 96 56                                      4510916 E 4 6.1 ≈30 >4.9 55 8 28                                    haloperidol                                                                             0.19     0.4      2.1 3  3860                                                                              19                                       clozapine 3.3 12.3 3.7 159 647 35                                           __________________________________________________________________________

It is evident from the ED₅₀ values of inhibition of the APO-inducedclimbing inhibition shown in Table 1 that most of the compounds inhibitthe APO-induced climbing already in a low oral dose (0.8-10 mg/kg), aresult supporting the in vivo antipsychotic activity of the compounds.The most active compound No. 4510470 is of ten-fold oral activity ascompared to clozapine, but several other molecules, such as thecompounds Nos. 4510408, 4510411 or 4510472, have ED₅₀ values lower thanor equal to that of clozapine. Simultaneously, the apomorphine-inducedstereotypy measured by the occurrence of sniffing in this case wasprevented only in significantly higher doses usually above 30 mg/kg ofthe compounds according to the invention. The above results, includingthe sniffing/climbing ratio, confirm the compounds' limbic selectivityin vivo and this selectivity is better than that of clozapine. Based onthe limbic selectivity, the action of the compounds is similar to thatof atypical antipsychotics, thus, the occurrence of extrapyramidalsymptoms (EPS) cannot be expected or only in higher doses.

The mechanism of action based on results of receptor binding assaysshown in Table 1. provide further support to the atypical antipsychoticnature of the compounds of the invention. Thus, their D-2 dopaminereceptor activity is less marked than the effect of the typicalantipsychotic haloperidol (3 nM) and indicates similarity rather to theatypical antipsychotic clozapine. However, the compounds according tothe invention are somewhat more effective on this receptor subtype.Their clozapine-like α-adrenerg receptor activity provides furtherevidence for their atypical features. The compounds in general as wellas their representatives, such as molecules No. 4510916 and No. 4510991,exert especially strong activity on 5-HT1A receptor subtypes. Thiseffect is significantly different from the weak 5-HT1A receptor activityof clozapine and similarly, it is different from the strength ofactivity of other atypical antispychotics which have been commerciallyavailable up to the present. This difference is even more markedlyexpressed by the D-2/5-HT1A ratio. For example, this ratio is 0.2 forclozapine, whereas it is 1.9 for the compound No. 4510470 and is even6.9 for the compound No. 4510916. The 5-HT1A receptor activity indicatesalso an anxiolytic effect component of the compounds.

In summary: the novel compounds of the invention are atypicalantipsychotics, which are essentially more active than clozapine afteroral administration. Similarly to clozapine, they possess a complexreceptor profile, however, receptor subtypes and their strength ofactivity involved participating in the mechanism of action of thecompounds are different from those of clozapine. Thus, the compounds ofthe invention are endowed of other character and new sort of complexprofile of mechanism of action. Therefore, the compounds according tothe invention could be very effective in the treatment of acute andchronic schizophrenia; paranoia and other psychotic disturbances;organic mental disorders, such as delirium, dementia. withdrawalsyndromes, addictions, mental retardation, tic disorders; affectivedisorders, such as mania, bipolar disorders, cyclothymia, dysthymia;anxiety disorders, including panic disorders, phobia,obsessive-compulsive disorders, generalized anxiety syndrome andpersonality disorders, such as compulsive, paranoid, schizoid,antisocial and any other disorders related to psychomotor agitation. Theexpected therapeutical doses of the compounds are between 0.01 and 50mg/kg of body weight, once or in repeated subdoses daily, administeredorally, intraperitoneally or subcutaneously route.

The preparation of the novel compounds of formula (I) according to theinvention are hereinafter described in detail.

The haloalkyl ether derivatives of formula (III), preferably2-chloroalkyl ether derivative known from the literature or prepared byknown methods, are reacted with the similarly known(2-methoxyphenyl)piperazin or a salt thereof, preferably with thecommercially available (2-methoxyphenyl)piperazin dihydrochloride in anorganic protic solvent, e.g. in an alcohol or in any organicdipolar-aprotic solvent, such as an aliphatic ketone; or acetonitrile,dimethylformamide and the like, optionally in the presence of a base andan alkaline metal iodide, such as sodium iodide. Suitable bases areinorganic bases, e.g. potassium carbonate, sodium carbonate; or organicbases, e.g. triethylamine. The reaction is carried out at the boilingpoint of the solvent used, for a reaction time of 5 to 10 hours. Afterevaporation of the reaction mixture containing the compound of formula(I), treating the dry residue with water and extracting the obtainedmixture with a water-immiscible solvent, the crude target compound offormula (I) is obtained, which can be purified by recrystallization ifnecessary.

If desired, the compounds of formula (I) can be converted to their acidaddition salts in a manner known per se.

The salt formation is accomplished in a known manner in an inert organicsolvent or solvent mixture in such a way that the compound of formula(I) is dissolved in the selected solvent and subsequently, theappropriate acid is added in portions to the above solution until themixture becomes strongly acidic (about pH 1 value). Alternatively, thesalt formation can be performed by adding the solution of the acid inthe calculated amount in the selected solvents to the above solution.Thereafter, the precipitated acid addition salt is separated from thereaction mixture in a suitable manner, e.g. by filtration.

The active ingredient of formula (I) can be transformed topharmaceutical compositions by mixing it with nontoxic, inert solid orliquid carriers commonly used in the therapy for parenteral or enteraladministration. E.g. water, gelatin, lactose, starch, pectin, magnesiumstearate, stearic acid, talc, vegetable oils such as olive oil or peanutoil and the like are useful carriers. The active ingredient may beformulated in the form of usual pharmaceutical compositions,particularly in solid form, e.g. as tablets, dragees, capsules, pills,suppository and the like. The amount of the solid carrier may be variedwithin wide limits, preferably between about 25 mg and 1 g. Thesecompositions may optionally contain the commonly used pharmaceuticalauxiliaries (additives), e.g. preservatives, stabilizing, wetting,emulsifying agents or the like. The preparation of these compositionscan be accomplished by common methods, e.g. by sieving, mixing,granulating and then compressing the components in the case of solidcompositions. The compositions may be exposed to further usualoperations, e.g. sterilization.

The invention is illustrated in detail by the following non-limitingexamples.

EXAMPLE 1 1-(2-Methoxyphenyl)-4-{2-[4-(2-indolizinyl)phenoxy]ethyl}piperazine

[Formula (I), Q=2-indolizinyl, n=2]

A mixture containing 2.72 g (10 mmol) of2-[4-(2-indolizinyl)phenoxy]ethyl chloride, 2.74 g (12 mmol) of(2-methoxyphenyl)piperazine dihydrochloride, 2.54 g (24 mmol) of sodiumcarbonate, 0.3 g (2 mmol) of anhydrous sodium iodide and 40 ml of methylisobutyl ketone is boiled under reflux for 10 hours. After evaporatingthe solvent under reduced pressure, the residue is thoroughly trituratedwith 20 ml of water, then extracted with 80 ml of chloroform. Theorganic phase is twice washed with 15 ml of water each, dried overanhydrous sodium sulfate and the drying agent is filtered off. Thefiltrate is stirred with 1 g of charcoal and 0.5 g of aluminium oxidefor 20 minutes, then filtered and evaporated to its half volume underreduced pressure. After adding 40 ml of ethanol to the residue, it isevaporated to about 15 ml under reduced pressure. The precipitatedmaterial is filtered and dried. The obtained 2.9 g crude product isdissolved in 30 ml of chloroform, 30 ml of ethanol are added then, thesolution obtained is evaporated to about 15 ml under reduced pressure.After filtering and drying the precipitated substance, the titlecompound is obtained in a yield of 2.61 g (61%), m.p.: 159-161° C.

EXAMPLE 21-(2-Methoxyphenyl)-4-{3-[4-(2-indolizinyl)phenoxy]propyl}piperazine

[Formula (I), Q=2-indolizinyl, n=3]

The procedure described in Example 1 is followed, except that3-[4-(2-indolizinyl)phenoxy]propyl chloride is used as starting materialinstead of 2-[4-(2-indolizinyl)phenoxy]ethyl chloride. The titlecompound melts at 157-158° C.

EXAMPLE 31-(2-Methoxyphenyl)-4-{4-[4-(2-indolizinyl)phenoxy]butyl}piperazine

[Formula (I), Q=2-indolizinyl, n=4], compound No. 4510613

The procedure described in Example 1 is followed, except that4-[4-(2-indolizinyl)phenoxy]butyl chloride is used as starting materialinstead of 2-[4-(2-indolizinyl)phenoxy]ethyl chloride. The titlecompound melts at 153-155° C.

EXAMPLE 41-(2-Methoxyphenyl)-4-{2-[4-(2-imidazo[1,2-a]pyridinyl)phenoxy]ethyl}piperazine

[Formula (I), Q=2-imidazo[1,2-a]pyridinyl, n=2], compound No. 4510408

The procedure described in Example 1 is followed, except that2-[4-(2-imidazo[1,2-a]pyridinyl)phenoxy]ethyl chloride is used asstarting material instead of 2-[4-(2-indolizinyl)phenoxy]ethyl chloride.The title compound melts at 151-153° C.

EXAMPLE 51-(2-Methoxyphenyl)-4-{3-[4-(2-imidazo[1,2-a]pyridinyl)phenoxy]propyl}piperazine

[Formula (I), Q=2-imidazo[1,2-a]pyridinyl, n=3], compound No. 4510067

The procedure described in Example 1 is followed, except that3-[4-(2-imidazo[1,2-a]pyridinyl)phenoxy]propyl chloride is used asstarting material instead of 2-[4-(2-indolizinyl)phenoxy]ethyl chloride.The title compound melts at 149-150° C.

EXAMPLE 61-(2-Methoxyphenyl)-4-{4-[4-(2-imidazo[1,2-a]pyridinyl)phenoxy]butyl}piperazine

[Formula (I), Q=2-imidazo[1,2-a]pyridinyl, n=4], compound No. 4510915

The procedure described in Example 1 is followed, except that4-[4-(2-imidazo[1,2-a]pyridinyl)phenoxy]butyl chloride is used asstarting material instead of 2-[4-(2-indolizinyl)phenoxy]ethyl chloride.The title compound melts at 144-145° C.

EXAMPLE 71-(2-Methoxyphenyl)-4-{2-[4-(2-imidazo[1,2-a]pyrimidinyl)phenoxy]ethyl}piperazine

[Formula (I), Q=2-imidazo[1,2-a]pyrimidinyl, n=2], compound No.4510911

The procedure described in Example 1 is followed, except that2-[4-(2-imidazo[1,2-a]pyrimidinyl)phenoxy]ethyl chloride is used asstarting material instead of 2-[4-(2-indolizinyl)phenoxy]ethyl chloride.The title compound melts at 150-152° C.

EXAMPLE 81-(2-Methoxyphenyl)-4-{3-[4-(2-imidazo[1,2-a]pyrimidinyl)phenoxy]propyl}piperazine

[Formula(I), Q=2-imidazo[1,2-a]pyrimidinyl, n=3], compound No. 4510924

The procedure described in Example 1 is followed, except that3-[4-(2-imidazo[1,2-a]pyrimidinyl)phenoxy]propyl chloride is used asstarting material instead of 2-[4-(2-indolizinyl)phenoxy]ethyl chloride.The title compound melts at 156-158° C.

EXAMPLE 91-(2-Methoxyphenyl)-4-{4-[4-(2-imidazo[1,2-a]pyrimidinyl)phenoxy]butyl}piperazine

[Formula(l), Q=2-imidazo[1,2-a]pyrimidinyl, n=4], compound No. 4510645

The procedure described in Example 1 is followed, except that4-[4-(2-imidazo[1,2-a]pyrimidinyl)phenoxy]butyl chloride is used asstarting material instead of 2-[4-(2-indolizinyl)phenoxy]ethyl chloride.The title compound melts at 151-153° C.

EXAMPLE 101-(2-Methoxyphenyl)-4-{2-[4-[6-(2,3-dihydroimidazo[2,1-b]thiazol)yl]phenoxy]ethyl}piperazine

[Formula (I), Q=6-(2,3-dihydroimidazo[2,1-b]thiazol)yl, n=2],

The procedure described in Example 1 is followed, except that2-{4-[6-(2,3-dihydroimidazo[2,1-b]thiazol)yl]phenoxy}ethtyl} chlorid isused as starting material instead of 2-[4-(2-indolizinyl)phenoxy]ethylchloride. The title compound melts at 145-147° C.

EXAMPLE 111-(2-Methoxyphenyl)-4-{3-[4-[6-(2,3-dihydroimidazo[2,1-b]thiazol)yl]phenoxy]jpropyl}piperazine

[Formula (I), Q=6-(2,3-dihydroimidazo[2,1-b]thiazol)yl, n=3], compoundNo.4510473

The procedure described in Example 1 is followed, except that3-{4-[6-(2,3-dihydroimidazo[2,1-b]thiazol)-yl]phenoxy}propyl chlorid isused as starting material instead of 2-[4-(2-indolizinyl)phenoxy]ethylchloride. The title compound melts at 142-144° C.

EXAMPLE 121-(2-Methoxyphenyl)-4-{4-[4-[6-(2,3-dihydroimidazo[2,1-b]thiazol)-yl]phenoxy]butyl}piperazine

[Formula (I), Q=6-(2,3-dihydroimidazo[2,1-b]thiazol)-yl, n=4], compoundNo. 4510991

The procedure described in Example 1 is followed, except that4-{4-[6-(2,3-dihydroimidazo[2,1-b]thiazol)-yl]phenoxy}butyl chlorid isused as starting material instead of 2-[4-(2-indolizinyl)phenoxy]ethylchloride. The title compound melts at 139-140° C.

EXAMPLE 131-(2-Methoxyphenyl)-4-{2-[4-[6-(imidazo[2,1-b]thiazolyl]phenoxy]ethyl}piperazine

[Formula (I), Q=6-imidazo[2,1-b]thiazolyl, n=2],

The procedure described in Example 1 is followed, except that2-{4-[6-imidazo[2,1-b]thiazolyl]phenoxy}ethtyl chlorid is used asstarting material instead of 2-[4-(2-indolizinyl)phenoxy]ethyl chloride.The title compound melts at 158-161° C.

EXAMPLE 141-(2-Methoxyphenyl)-4-{3-[4-[6-imidazo[2,1-b]thiazolyl)phenoxy]propyl}piperazine

[Formula (I), Q=6-imidazo[2,1-b]thiazolyl, n=3], compound No. 4510472

The procedure described in Example 1 is followed, except that3-[4-(6-imidazo[2,1-b]thiazolyl)phenoxy]propyl chloride is used asstarting material instead of 2-[4-(2-indolizinyl)phenoxy]ethyl chloride.The title compound melts at 130-132° C.

EXAMPLE 151-(2-Methoxyphenyl)-4-{4-[4-[6-imidazo[2,1-b]thiazolyl)phenoxy]butyl}piperazine

[Formula (I), Q=6-imidazo[2,1-b]thiazolyl, n=4]

The procedure described in Example 1 is followed, except that4-[4-[6-imidazo[2,1-b]thiazolyl)phenoxy]butyl chloride is used asstarting material instead of 2-[4-(2-indolizinyl)phenoxy]ethyl chloride.The title compound melts at 128-130° C.

EXAMPLE 161-(2-Methoxyphenyl)-4-{2-[4-(2-indolizinyl)phenoxy]ethyl}piperazinedihydrochloride

[Formula (I), Q=2-indolizinyl, n=2], compound No. 4510407

After dissolving 21.5 g (0.05 mol) of1-(2-methodyphenyl)-4-{2-[4-(2-indolizinyl)phenoxy]ethyl piperazine(prepared as described in Example 1) in 50 ml of chloroform, 50 ml ofethanol are added to the solution, then the reaction mixture isacidified to pH 1 by adding 20 to 30% ethanolic hydrochloric acid. Theprecipitate is filtered, washed with a little amount of ethanol anddried to yield 24.5 g (98%) of title compound, m.p. 220-222° C.

EXAMPLE 171-(2-Methoxyphenyl)-4-{3-[4-[2-indolizinyl)phenoxy]propyl}piperazinedihydrochloride

[Formula (I), Q=2-indolizinyl, n=3], compound No. 4510423

The procedure described in Example 16 is followed, except that1-(2-methoxyphenyl)-4-{3-[4-(2-indolizinyl)phenyoxy]propyl}piperazine isused as starting substance instead of1-(2-methoxyphenyl)-4-{2-[4-(2-indolizinyl)phenoxy]ethyl}piperazine. Thetitle compound melts at 239-241° C.

EXAMPLE 181-(2-Methoxyphenyl)-4-{2-[4-[6-(2,3-dihydroimidazo[2,1-b]thiazol)-yl]phenoxy]ethyl}piperazinetrihydrochloride

[Formula (I), Q=6-(2,3-dihydroimidazo[2,1-b]thiazol)-yl, n=2], compoundNo. 4510471

The procedure described in Example 16 is followed, except that1-(2-methoxyphenyl)-4-{2-[4-(6-(2,3-dihydroimidazo[2,1-b]thiazol)-yl]phenoxy}ethylpiperazine is used as starting substance instead of1-(2-methoxyphenyl)-4-{2-[4-(2-indolizinyl)phenoxy]jethyl}piperazine.The title compound melts at 214-216° C.

EXAMPLE 191-(2-Methoxyphenyl)-4-{2-[4-[6-imidazo[2,1-b]thiazolyl]phenoxy]ethyl}piperazinetrihydrochloride

[Formula (I), Q=6-imidazo[2,1-b]thiazolyl, n=2], compound No. 4510470

The procedure described in Example 16 is followed, except that1-(2-methoxyphenyl)-4-{2-[4-(6-imidazol[2,1-b]thiazolyl]phenoxy]ethyl}piperazineis used as starting material instead of1-(2-methoxyphenyl)-4-{2-[4-(2-indolizinyl) phenoxy]ethyl}piperazine.The title compound melts at 254-256° C.

EXAMPLE 201-(2-Methoxyphenyl)4-{4-[4-[6-imidazo[2,1-b]thiazolyl]phenoxy]butyl}piperazinetrihydrochloride

[Formula (I), Q=6-imidazo[2,1-b]thiazolyl, n=4], compound No. 4510916

The procedure described in Example 16 is followed, except that1-(2-methoxyphenyl)-4-{4-[4-(6-imidazol[2,1-b]thiazolyl]phenoxy]ethyl}piperazineis used as starting material instead of1-(2-methoxyphenyl)-4-{2-[4-(2-indolizinyl)phenoxy]ethyl}PIPERAZINE. Thetitle compound melts at 227-229° C.

What is claimed is:
 1. A compound of the Formula (I) ##STR5## wherein Qis 2-indolizinyl, 2-imidazo{1,2-a}pyridinyl,2-imidazo{1,2-a}pyrimidinyl, 6-(2,3-dihydroimidazo[2,1-b}thiazol)-yl or6-imidazo{2,1-b}thiazol)-yl; andn is an integer of 2 to 4; or atherapeutically acceptable salt thereof.
 2. The compound of the Formula(I) defined in defined in claim 1 wherein Q is 2-imidazo{1,2-a}pyridinylor 6-imidazo{2,1-b}thiazol)-yl or a therapeutically acceptable saltthereof.
 3. The compound of the Formula (I) defined in claim 1 selectedfrom the group consisting of:(a)1-(2-methoxyphenyl)-4-{2-[4-(6-imidazo{2,1-b}thiazolyl)phenoxy]ethyl}piperazine; (b)1-(2-methoxyphenyl)-4-{2-[4-(2-imidazo{1,2-a}pyridinyl)phenoxy]ethyl}piperazine; (c)1-(2-methoxyphenyl)-4-{4-[4-(6-(2,3-dihydroimidazo{2,1-b}thiazol)-yl)phenoxy]butyl}piperazine; (d)1-(2-methoxyphenyl)-4-{3-{4-(6-imidazo{2,1-b}thiazolyl)phenoxy]propyl}piperazine; (e)1-(2-methoxyphenyl)-4-{4-[4-(6-imidazo{2,1-b}thiazol)-yl)phenoxy]butyl}piperazine; and (f)1-(2-methoxyphenyl)-4-{(2-[4-(2-imidazo{1,2-a}pyrimidinyl)phenoxy]ethyl}piperazine, or a therapeutically is acceptable salt thereof as definedin claim
 1. 4. A pharmaceutical composition for treating a psychosiswhich comprises as active ingredient, a therapeutically effective amountof the compound of the Formula (I) defined in claim 1 or atherapeutically acceptable salt thereof.
 5. A process for preparing acompound of the Formula (I): ##STR6## wherein Q is 2-indolizinyl,2-imidazo{1,2-a}pyridinyl, 2-imidazo{1,2-a}pyrimidinyl,6-(2,3-dihydroimidazo[2,1-b}thiazol)-yl or 6-imidazo{2,1-b}thiazol)-yl;or a pharmaceutically acceptable salt thereof, andn is an integer from 2to 4, which comprises the step of N-alkylating a compound of the Formula(III) ##STR7## or a salt thereof with a compound of the Formula (II)##STR8## wherein X is halogen in an organic solvent, to obtain thecompound of the Formula (I) and where a therapeutically acceptable saltof the Formula (I) is desired converting the compound of the Formula (I)to a therapeutically acceptable salt.
 6. The process for preparing acompound of the Formula (I) defined in claim 5 wherein the N-alkylationof the compound of the Formula (III) with the compound of the Formula(II) is carried out in the presence of an alkali iodide.
 7. A method oftreating a psychosis in a patient which comprises the step ofadministering to said patient, a therapeutically effective amount of thecompound of the Formula (I) defined in claim 1 or a therapeuticallyacceptable salt thereof.